RESUMEN
A series of pyrazole-based thioethers were prepared and found to be potent cathepsin S inhibitors. A crystal structure of 13 suggests that the thioether moiety may bind to the S3 pocket of the enzyme. Additional optimization led to the discovery of aminoethylthioethers with improved enzymatic activity and submicromolar cellular potency.
Asunto(s)
Catepsinas/antagonistas & inhibidores , Catepsinas/metabolismo , Inhibidores de Proteasas/farmacología , Pirazoles/farmacología , Sulfuros/farmacología , Sitios de Unión , Catepsinas/química , Línea Celular , Cristalografía por Rayos X , Humanos , Modelos Moleculares , Inhibidores de Proteasas/química , Pirazoles/química , Relación Estructura-Actividad , Sulfuros/químicaRESUMEN
Three series of H(4) receptor ligands, derived from indoly-2-yl-(4-methyl-piperazin-1-yl)-methanones, have been synthesized and their structure-activity relationships evaluated for activity at the H(4) receptor in competitive binding and functional assays. In all cases, substitution of small lipophilic groups in the 4 and 5-positions led to increased activity in a [(3)H]histamine radiolabeled ligand competitive binding assay. In vitro metabolism and initial pharmacokinetic studies were performed on selected compounds leading to the identification of indole 8 and benzimidazole 40 as potent H(4) antagonists with the potential for further development. In addition, both 8 and 40 demonstrated efficacy in in vitro mast cell and eosinophil chemotaxis assays.
Asunto(s)
Antagonistas de los Receptores Histamínicos/síntesis química , Antagonistas de los Receptores Histamínicos/farmacología , Piperazinas/síntesis química , Piperazinas/farmacología , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Animales , Bencimidazoles/síntesis química , Bencimidazoles/farmacocinética , Bencimidazoles/farmacología , Unión Competitiva , Línea Celular Tumoral , Quimiotaxis de Leucocito/efectos de los fármacos , Eosinófilos/efectos de los fármacos , Antagonistas de los Receptores Histamínicos/farmacocinética , Humanos , Indoles/síntesis química , Indoles/farmacocinética , Indoles/farmacología , Mastocitos/efectos de los fármacos , Ratones , Piperazinas/farmacocinética , Ratas , Receptores Histamínicos , Receptores Histamínicos H4RESUMEN
Following the discovery of the human histamine H4 receptor, a high throughput screen of our corporate compound collection identified compound 6 as a potential lead. Investigation of the SAR resulted in the discovery of novel compounds 10e and 10l, which are the first potent and selective histamine H4 receptor antagonists to be described.
Asunto(s)
Antagonistas de los Receptores Histamínicos/química , Antagonistas de los Receptores Histamínicos/farmacología , Piperazinas/química , Piperazinas/farmacología , Receptores de Superficie Celular/efectos de los fármacos , Receptores Acoplados a Proteínas G , Receptores Histamínicos , Animales , Línea Celular , Relación Dosis-Respuesta a Droga , Antagonistas de los Receptores Histamínicos/metabolismo , Humanos , Indoles/química , Indoles/metabolismo , Indoles/farmacología , Cinética , Ligandos , Neuronas/citología , Piperazinas/metabolismo , Ensayo de Unión Radioligante , Ratas , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/metabolismo , Receptores Histamínicos H4 , Proteínas Recombinantes/efectos de los fármacos , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Relación Estructura-Actividad , TransfecciónRESUMEN
BACKGROUND: Histamine is a potent mediator of itch in humans, yet histamine H(1) receptor antagonists have been shown to be of limited use in the treatment of certain chronic pruritic diseases. The histamine H(4) receptor is a recently described histamine receptor, expressed on hematopoietic cells, linked to the pathology of allergy and asthma. OBJECTIVE: The contribution of the novel histamine H(4) receptor to histaminergic and allergic pruritus was investigated. RESULTS: Histamine and a selective histamine H(4) receptor agonist caused scratching responses in mice, which were almost completely attenuated in histamine H(4) receptor knockout mice or by pretreatment with the selective histamine H(4) receptor antagonist, JNJ 7777120. Pruritus induced by allergic mechanisms was also potently inhibited with histamine H(4) receptor antagonist treatment or in histamine H(4) receptor knockout mice. In all cases, the inhibitory effect of histamine H(4) receptor antagonist was greater than those observed with histamine H(1) receptor antagonists. The histamine H(4) receptor-mediated pruritus was shown to be independent of mast cells or other hematopoietic cells and may result from actions on peripheral neurons. CONCLUSION: These results demonstrate that the histamine H(4) receptor is involved in pruritic responses in mice to a greater extent than the histamine H(1) receptor. CLINICAL IMPLICATIONS: Histamine H(4) receptor antagonists may have therapeutic utility for treating chronic pruritic diseases in humans where histamine H(1) receptor antagonists are not effective.
Asunto(s)
Antagonistas de los Receptores Histamínicos/farmacología , Indoles/farmacología , Piperazinas/farmacología , Prurito/tratamiento farmacológico , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Animales , Modelos Animales de Enfermedad , Edema/inducido químicamente , Femenino , Pie , Histamina , Agonistas de los Receptores Histamínicos/farmacología , Mastocitos/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Prurito/inducido químicamente , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/deficiencia , Receptores Acoplados a Proteínas G/genética , Receptores Histamínicos/deficiencia , Receptores Histamínicos/genética , Receptores Histamínicos H1/metabolismo , Receptores Histamínicos H4RESUMEN
A series of 2-arylbenzimidazoles was synthesized and found to bind with high affinity to the human histamine H(4) receptor. Structure-activity relationships were investigated through library preparation and evaluation as well as traditional medicinal chemistry approaches, leading to the discovery of compounds with single-digit nanomolar affinity for the H(4) receptor.
Asunto(s)
Bencimidazoles/síntesis química , Bencimidazoles/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores Histamínicos/metabolismo , Aldehídos/química , Aminas/química , Bencimidazoles/química , Catálisis , Simulación por Computador , Histamina/metabolismo , Humanos , Ligandos , Modelos Moleculares , Estructura Molecular , Unión Proteica , Receptores Acoplados a Proteínas G/química , Receptores Histamínicos/química , Receptores Histamínicos H4 , Relación Estructura-ActividadRESUMEN
The diverse physiological functions of histamine are mediated through distinct histamine receptors. Mast cells are major producers of histamine, yet effects of histamine on mast cells are currently unclear. The present study shows that histamine induces chemotaxis of mouse mast cells, without affecting mast cell degranulation. Mast cell chemotaxis toward histamine could be blocked by the dual H3/H4 receptor antagonist thioperamide, but not by H1 or H2 receptor antagonists. This chemotactic response is mediated by the H4 receptor, because chemotaxis toward histamine was absent in mast cells derived from H4 receptor-deficient mice but was detected in H3 receptor-deficient mast cells. In addition, Northern blot analysis showed the expression of H4 but not H3 receptors on mast cells. Activation of H4 receptors by histamine resulted in calcium mobilization from intracellular calcium stores. Both G alpha i/o proteins and phospholipase C (PLC) are involved in histamine-induced calcium mobilization and chemotaxis in mast cells, because these responses were completely inhibited by pertussis toxin and PLC inhibitor 1-[6-[[17 beta-3-methoxyestra-1,3,5 (10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione (U73122). In summary, histamine was shown to mediate signaling and chemotaxis of mast cells via the H4 receptor. This mechanism might be responsible for mast cell accumulation in allergic tissues.
Asunto(s)
Calcio/metabolismo , Mastocitos/metabolismo , Receptores Acoplados a Proteínas G , Receptores Histamínicos/metabolismo , Animales , Basófilos/metabolismo , Células Cultivadas , Quimiotaxis , Eosinófilos/metabolismo , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/metabolismo , Histamina/metabolismo , Humanos , Ratones , Ratones Noqueados , Receptores Histamínicos H4 , Fosfolipasas de Tipo C/metabolismoRESUMEN
Histamine mediates its physiological function through binding to four known histamine receptors. Here, we describe the first selective antagonist of the histamine H4 receptor, the newest member of the histamine receptor family, and provide evidence that such antagonists have anti-inflammatory activity in vivo. 1-[(5-chloro-1H-indol-2-yl)carbonyl]-4-methylpiperazine (JNJ 7777120) has a K(i) of 4.5 nM versus the human receptor and a pA(2) of 8.1. It is equipotent against the human, mouse, and rat receptors. It exhibits at least 1000-fold selectivity over H1, H2, or H3 receptors and has no cross-reactivity against 50 other targets. This compound has an oral bioavailability of approximately 30% in rats and 100% in dogs, with a half-life of approximately 3 h in both species. JNJ 7777120 blocks histamine-induced chemotaxis and calcium influx in mouse bone marrow-derived mast cells. In addition, it can block the histamine-induced migration of tracheal mast cells from the connective tissue toward the epithelium in mice. JNJ 7777120 significantly blocks neutrophil infiltration in a mouse zymosan-induced peritonitis model. This model is reported to be mast cell-dependent, which suggests that the compound effect may be mediated by mast cells. These results indicate that the histamine H4 receptor plays a role in the inflammatory process. Selective H4 receptor antagonists like JNJ 7777120 may have the potential to be useful in treating inflammation in humans.